Exploiting the Nucleotide Substrate Specificity of Repair DNA Polymerases To Develop Novel Anticancer Agents.docVIP

Molecules 2011, 16, 7994-8019; doi:10.3390/moleculeOPEN ACCESS molecules ISSN 1420-3049 /journal/molecules Review Exploiting the Nucleotide Substrate Specificity of Repair DNA Polymerases To Develop Novel Anticancer Agents Emmanuele Crespan, Anna Garbelli, Alessandra Amoroso and Giovanni Maga * DNA Enzymology Molecular Virology, Insititute of Molecular Genetics IGM-CNR, via Abbiategrasso 207, I-27100 Pavia, Italy; E-Mails: emmanuelecrespan@ (E.C.); agarbelli@ (A.G.); alyahoo.it (A.A.) * Author to whom correspondence should be addressed; E-Mail: maga@r.it; Tel.: +39-0382546354; Fax: +39-0382422286. Received: 5 July 2011; in revised form: 26 August 2011 / Accepted: 13 September 2011 / Published: 16 September 2011 Abstract: The genome is constantly exposed to mutations that can originate during replication or as a result of the action of both endogenous and/or exogenous damaging agents [such as reactive oxygen species (ROS), UV light, genotoxic environmental compounds, etc.]. Cells have developed a set of specialized mechanisms to counteract this mutational burden. Many cancer cells have defects in one or more DNA repair pathways, hence they rely on a narrower set of specialized DNA repair mechanisms than normal cells. Inhibiting one of these pathways in the context of an already DNA repair-deficient genetic background, will be more toxic to cancer cells than to normal cells, a concept recently exploited in cancer chemotherapy by the synthetic lethality approach. Essential to all DNA repair pathways are the DNA pols. Thus, these enzymes are being regarded as attractive targets for the development of specific inhibitors of DNA repair in cancer cells. In this review we examine the current state-of-the-art in the development of nucleotide analogs as inhibitors of repair DNA polymerases. Keywords: DNA repair; cancer; DNA polymerase; nucleoside analogs  Molecules 2011, 16 7995 1